The overall goal of this mentored research project is to provide the candidate with the opportunity to develop the knowledge and technical and interpretive skills required to pursue his long-term career goal of becoming an independent academic surgeon. Five years have elapsed since the candidate obtained his formal research training. A transitional period, under the guidance of mentors, that involves course work, attendance at seminars, conducting experiments, and preparing manuscripts and grants will allow the candidate to make a smooth transition to independent investigator. The objective of the proposed studies is to study the regulation of modulated intestinal glutamine transport in sepsis. Sepsis, a common problem in surgery, causes intestine dysfunction and is associated with substantial morbidity and mortality. Transport of luminal glutamine is key in maintaining intestinal integrity and functions in sepsis. Animal studies and clinical trials have demonstrated that glutamine reduces sepsis-related intestinal dysfunction and death, but little is known about the mechanism by which sepsis regulates the intestinal glutamine transport. A better understanding of this mechanism will allow for a better development of treatment modalities. Based on our preliminary studies, we hypothesize that sepsis stimulates intestinal glutamine transport capacity by enhancing the expression of the glutamine transporter ATB0 gene via activation of protein kinase C, mitogen-activated protein kinases, and nuclear factors, resulting in an increase of cellular glutamine which prevents sepsis-related gut dysfunction. The specific studies test the hypotheses are: 1) To determine whether systemic infection increases intestinal glutamine transport activity in rats, 2) To identify the role of pro-inflammatory cytokines and endotoxin on regulation of glutamine transport activity and gene expression, 3) To define the intracellular signaling pathway(s) responsible for the regulation of glutamine transport in sepsis, 4) To assess the effect of glutamine on membrane glutamine transport and determine whether providing exogenous glutamine prevents the endotoxin or cytokine-induced increase in intestinal mucosal permeability. In conducting these studies, the candidate will obtain the experience and expertise necessary to become an independent investigator.